PIKFYVE inhibition mitigates disease in models of diverse forms of ALS

Hung, Shu‐Ting; Linares, Gabriel; Chang, Wen-Hsuan; Eoh, Yunsun; Krishnan, Gopinath; Mendonca, Stacee; Hong, Sarah; Shi, Yuanjie; Santana, Manuel; Macklin-Isquierdo, Samantha; Perry, Sarah L.; Duhaime, Sarah; Maios, Claudia; Chang, Jonathan; Perez, Joscany; Couto, Alexander Benavides; Lai, Jesse D.; Li, Yichen; Alworth, Samuel V.; Hendricks, Eric; Wang, Yaoming; Zloković, Berislav V.; Dickman, Dion; Parker, J. Alex; Zarnescu, Daniela C.; Gao, Fen‐Biao; Ichida, Justin K.

doi:10.1016/j.cell.2023.01.005

Cited by 42 publications

(34 citation statements)

References 69 publications

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“…A recent research showed that the inhibition of PIKfyve, a phosphoinositide kinase, could mitigate disease and extends survival of the ALS mouse models. [60] The results of the KEGG enrichment analysis indicated that pathways involved including the Ras signaling pathway, the PI3K-Akt signaling pathway, the MAPK signaling pathway, and so on. The Ras proteins also known as GTPases act as molecular switches regulating multiple biological processes including cell survival, growth, proliferation, differentiation and cytoskeletal dynamism.…”

Section: Discussionmentioning

confidence: 99%

Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology

Tang,

Zhan,

Yang

et al. 2023

Medicine

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Semen Strychni (SS), known as an agonist of central nervous system, is a traditional herb widely used in treating amyotrophic lateral sclerosis (ALS) in small doses to relieve muscle weakness and improve muscle strength. However, the potential mechanisms and the main components of SS in treating ALS remain unclear. To explore the underlying mechanism of SS in treating ALS based on network pharmacology and molecular docking. The active components of SS were obtained using TCMSP, Herb, ETCM, and BATMAN-TCM. The targets of SS were gained from PharmMapper. The targets of ALS were searched on Genecards, Drugbank, DisGeNET, OMIM, TTD and GEO database. After obtaining the coincidence targets, we submitted them to the STRING database to build a protein-protein interaction network. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed subsequently. The active components and targets were further investigated using molecular docking technology. 395 targets of SS and 1925 targets of ALS were obtained with 125 common targets. The protein-protein interaction analysis indicated that SRC, AKT1, MAPK1, EGFR, and HSP90AA1 received the higher degree value and were considered the central genes. The Ras, PI3K-Akt, and MAPK signaling pathway could be involved in the treatment of ALS. Brucine-N-oxide obtained the lowest binding energy in molecular docking. This study explored the mechanism of SS in the treatment of ALS and provides a new perspective for future study. However, further experimental studies are needed to validate the therapeutic effect.

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Section: Discussionmentioning

confidence: 99%

Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology

Tang,

Zhan,

Yang

et al. 2023

Medicine

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“…Within the 28S rRNA, a prominent peak was located between nucleotides 2744 and 2810. This 66-nucleotide (nt) region was the most highly enriched site in both CLIP experiments, accounting for 30% and 45% of total reads in the GFP-(GR) 50 samples. An additional 57-nt peak at the 3 0 end of the 5.8S rRNA accounted for approximately 7% and 9% of the reads in the two GFP-(GR) 50 datasets.…”

Section: Poly-gr Binds To Rrna In Cellsmentioning

confidence: 99%

“…To validate the selective interaction between rRNAs and (GR) 50 relative to other C9-DPRs, we performed RIP RT-qPCR analysis in cells transfected with GFP-(GR) 50 or GFP-(GA) 50 . These experiments revealed that 18S, 28S, and ITS1 rRNAs were again significantly enriched within the GFP-(GR) 50 immunoprecipitates relative to GFP-(GA) 50 (fig.…”

Section: Poly-gr Binds To Rrna In Cellsmentioning

confidence: 99%

CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against C9ORF72 ALS/FTD poly-GR pathophysiology

Ortega,

Sasselli,

Boccitto

et al. 2023

Sci. Adv.

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Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in C9ORF72 (C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind low-complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remain unclear. Here, we used computational and experimental approaches to characterize the physicochemical properties of R-DPRs and their interaction with RNA. We find that poly-GR predominantly binds ribosomal RNA (rRNA) in cells and exhibits an interaction that is predicted to be energetically stronger than that for associated ribosomal proteins. Critically, modified rRNA “bait” oligonucleotides restore poly-GR–associated ribosomal deficits and ameliorate poly-GR toxicity in patient neurons and Drosophila models. Our work strengthens the hypothesis that ribosomal function is impaired by R-DPRs, highlights a role for direct rRNA binding in mediating ribosomal dysfunction, and presents a strategy for protecting against C9-HRE pathophysiological mechanisms.

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“…Another groups of compounds that appear to benefit the LYPAS through mild lysosomal stress are PIKfyve inhibitors. Although PIKfyve mutations can cause neurodegeneration, partial PIKfyve inhibition by small molecules, including the clinically available apilimod and YM201636, appears to ameliorate various neurodegenerative diseases (Shi et al , 2018; Soares et al , 2021; Hung et al , 2023). PIKfyve inhibition promoted neuronal survival and relieved neurodegeneration in diverse models of ALS both in vitro and in vivo , which appears to involve, at least in part, exocytosis of aggregation‐prone proteins (Shi et al , 2018; Hung et al , 2023).…”

Section: Introductionmentioning

confidence: 99%

“…Although PIKfyve mutations can cause neurodegeneration, partial PIKfyve inhibition by small molecules, including the clinically available apilimod and YM201636, appears to ameliorate various neurodegenerative diseases (Shi et al , 2018; Soares et al , 2021; Hung et al , 2023). PIKfyve inhibition promoted neuronal survival and relieved neurodegeneration in diverse models of ALS both in vitro and in vivo , which appears to involve, at least in part, exocytosis of aggregation‐prone proteins (Shi et al , 2018; Hung et al , 2023). In addition, PIKfyve inhibition suppresses the trafficking of endocytosed tau seeds to lysosomes and their subsequent cytosolic spreading, with no impact on their endocytosis (Soares et al , 2021).…”

Section: Introductionmentioning

confidence: 99%

Lysosomes in senescence and aging

Tan,

Finkel

2023

EMBO Reports

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Dysfunction of lysosomes, the primary hydrolytic organelles in animal cells, is frequently associated with aging and age‐related diseases. At the cellular level, lysosomal dysfunction is strongly linked to cellular senescence or the induction of cell death pathways. However, the precise mechanisms by which lysosomal dysfunction participates in these various cellular or organismal phenotypes have remained elusive. The ability of lysosomes to degrade diverse macromolecules including damaged proteins and organelles puts lysosomes at the center of multiple cellular stress responses. Lysosomal activity is tightly regulated by many coordinated cellular processes including pathways that function inside and outside of the organelle. Here, we collectively classify these coordinated pathways as the lysosomal processing and adaptation system (LYPAS). We review evidence that the LYPAS is upregulated by diverse cellular stresses, its adaptability regulates senescence and cell death decisions, and it can form the basis for therapeutic manipulation for a wide range of age‐related diseases and potentially for aging itself.

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PIKFYVE inhibition mitigates disease in models of diverse forms of ALS

Cited by 42 publications

References 69 publications

Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology

Exploring the mechanism of Semen Strychni in treating amyotrophic lateral sclerosis based on network pharmacology

CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against C9ORF72 ALS/FTD poly-GR pathophysiology

Lysosomes in senescence and aging

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